新型蓝萼甲素-1,2,3-三氮唑类衍生物的合成与抗增殖活性研究
收稿日期: 2022-05-28
修回日期: 2022-08-01
网络出版日期: 2022-08-18
基金资助
国家自然科学基金(21672182); 河南省科技攻关(212102311026); 河南省高等学校青年骨干教师培养计划(2021GGJS105); 国家大学生创新创业训练计划(S202210472047)
Synthesis and Antiproliferative Activity Evaluation of Novel Glaucocalyxin A-1,2,3-Triazole Derivatives
Received date: 2022-05-28
Revised date: 2022-08-01
Online published: 2022-08-18
Supported by
National Natural Science Foundation of China(21672182); Science and Technology Tackling Key Project of Henan Province(212102311026); Young Backbone Teacher Training Projects of Universities in Henan Province(2021GGJS105); National Undergraduate Training Program for In-novation and Entrepreneurship(S202210472047)
设计并合成了一系列新型的天然产物蓝萼甲素(Glaucocalyxin A, GLA)-1,2,3-三氮唑类衍生物, 并评估该系列衍生物对HepG2、NCI-H460、JEG-3、K562、HL-60和Hela等六种人肿瘤细胞株的抗增殖活性. 结果表明大多数化合物具有很强的抗增殖作用, 其中一些化合物的活性明显优于GLA. 其中(3S,3aR,3a1R,6aR,11aR)-5-(1-(4-羟基苯基)-1H-1,2,3-三唑-4-基)-8,8,11a-三甲基-13-亚甲基十氢-1H-3,3a1-乙吩并[1,10-de][1,3]二噁-9,12(2H)-二酮(16)对HL-60细胞株表现出最强的抑制作用(IC50=0.25 μmol•L－1), 其活性比阳性药阿霉素强6.9倍, 比蓝萼甲素强25.8倍. 这些结果表明在保留D环上α,β-不饱和酮药效基团的前提下, 间羟基或对羟基苯基取代的1,2,3-三氮唑缩醛结构片段的引入是提高蓝萼甲素抗肿瘤活性的有效途径. 细胞凋亡形态学和流式细胞仪测定表明蓝萼甲素-1,2,3-三氮唑类衍生物具有诱导肿瘤细胞凋亡的作用.
张涛 , 卫海沅 , 马雯 , 李张媛 , 胡盼盼 , 周楠茜 , 贺建超 , 李婷 , 苏明明 , 白素平 . 新型蓝萼甲素-1,2,3-三氮唑类衍生物的合成与抗增殖活性研究[J]. 有机化学, 2022 , 42(11) : 3668 -3683 . DOI: 10.6023/cjoc202205049
A series of novel 1,2,3-triazole derivatives based on natural product glaucocalyxin A (GLA) were designed and prepared. Their antiproliferative activity was evaluated against six human tumor cell lines (HepG2, NCI-H460, JEG-3, K562, HL-60, Hela). Most compounds exhibited potent antiproliferative effects with low micromolar IC50 values. The activity of some of the compounds is significantly superior to GLA. In particular, (3S,3aR,3a1R,6aR,11aR)-5-(1-(4-hydroxyphenyl)-1H- 1,2,3-triazol-4-yl)-8,8,11a-trimethyl-13-methylenedecahy-dro-1H-3,3a1-ethanophenanthro[1,10-de][1,3]dioxine-9,12(2H)-dione (16) displayed the highest inhibition efficacy (IC50=0.25 μmol•L－1), which was 6.9 times higher than that of the positive control adriamycin and 25.8 times higher than that of GLA against HL-60 cells. The results also demonstrated that the introduction of triazole acetal with meta- and para-hydroxyl substitution on phenyl without change of methylene cyclopentanone on the D-ring could improve the antitumor activity of GLA significantly. The apoptosis morphology and flow cytometry studies indicated that the triazole-fused GLA derivatives could induce apoptosis of tumor cells.
Key words： glaucocalyxin A; triazole; acetal derivative; antiproliferative activity
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